Inflammation-preventing pharmaceutical composition of oral administration

ABSTRACT

A novel pharmaceutical composition is provided which is suitable for the prevention of inflammation and which comprises non-steroidal inflammation-preventing compound (e.g. pyrazolones, salicylic acid derivatives, indoles, indanes, and phenylacetic acid and anthranilic acid derivatives) and at least one phospholipid.

This is a division of application Ser. No. 104,449 filed Dec. 17, 1979now U.S. Pat. No. 4,332,795.

BACKGROUND OF THE PRESENT INVENTION

A great number of substances for the effective treatment of inflammatoryillnesses, for example rheumatism, have been known for a long time.Since the inflammations are often chronic, the treatment with suchinflammation-preventing active substances will usually extend over along period of time. The non-steroidal antiphlogistic substances usedfor such continuous treatments very often have undesirable side effectson the digestive tract, such as, for example, in the form ofgastro-intestinal bleeding and stomach ulcers as described by Y. H. Leeet al in "Arch.int. Pharmacodyn." 191, 370-377 (1971) and by K. D.Rainsford in "Agents and Actions" 1977 7(5/6), 573-77, as well as by A.R. Cooke in "Drugs" 1976, vol. 11, pages 36 to 44.

Many attempts have been made to moderate the side effects of theseeffective non-steroidal antiphlogistic substances by the admixture of anadditional active substance. All mixtures of this type have thedisadvantage that the additional substance might cause an ulcer on itsown, or might even influence adversely the effectiveness of the primarynon-steriodal antiphlogistic substance.

Attempts have been made, for example, to admix anticholinergicsubstances or pepsin inhibitors with the antiphlogistic substances (Y.H. Lee et al, "Arch.int.Pharmacodyn," 191, 370-377 (1971)). The firm ofRichter Gedeon (DE-OS No. 25 24 902) proposed the admixture of salicylicacid salts with the antiphlogistic substances. However, salicylic acidsalts have analgetic and antiphologistic properties of their own and cancause strong side effects such as nausea and vomiting as well as damageof the mucous membrane of the stomach with the possibility of bleedingif administered over longer periods of time as reported by E. Mutschlerin "Arzneimittelwirkungen", wissenschaftliche Verlagsgesellschaft 1970,pages 76, 77.

The Sumitomo Chemical Co. Ltd. has proposed the combination ofnon-steroidal antiphlogistic substances with quinazolines (see DE-OS No.26 27 914) with the purpose of preventing the formation of peptic ulcerswithin the area of the digestive tract. However, these quinazolines aresubstances with an analgetic and antiphlogistic effect of their own.U.S. Pat. No. 3,993,767 describes mixtures of non-steroidalantiphlogistic substances with metaxalon. However, the metaxalon has amuscle-relaxing effect. See the Merck Index, Ninth edition 1976, page772.

OBJECTS AND SUMMARY OF THE INVENTION

It is therefor the object of the present invention to develop aninflammation-preventing medicine which will substantially improve thepoor compatibility of non-steroidal antiphlogistic substances withoutadversely influencing the inflammation-preventing effect of these activesubstances.

It has been found that serious side effects on the digestive tract suchas damage to the mucous membrane or gastric ulcer formation bynon-steroidal antiphlogistic substances can be prevented if thesesubstances are combined in a suitable manner with phospholipids. Themedicinal compositions of the present invention will therefore containthese antiphologistic substances in conjunction with phospholipids. Thephospholipids have the advantage over the previously describedsubstances in that they are body-inherent, can be readily broken downwithin the body, do not promote any side effects (even if administeredcontinuously (see J. Weihrauch, U.S. Dept. of Agriculture, quoted inNational Enquirer of June 6, 1978, page 33)) and do not possess anyanalgetic or antiphlogistic effect of their own. The admixture ofphospholipids with non-steroidal antiphlogistic substances substantiallylowers the degree of side effects while the analgetic and antiphlogisticproperties remain intact.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

Natural as well as synthetic phospholipids can be used in thepreparations of the present invention. Natural phospholipids (of plantor animal origin) such as phosphatidylcholine, phosphatidylethanolamine,phosphatidylinositol, phosphatidylserine, sphingomyeline, cephaline,lysolecithin, phosphatidylglycol, cardiolipin, and plasmalogens (whichcan all be obtained, for example, from the soya bean or egg) andmixtures of these phospholipids are suitable for use in the presentinvention. Commercially available phosphatidylcholines orphosphatidylcholine-mixtures include Phospholipon® 100, Phospholipon®100H, Phospholipon® 80 and Phospholipon® 45. Usable syntheticphosphatides include, for example, ditetradecanoylphosphatidylcholine,dihexadecanoylphosphatidylcholine, dioleylphosphatidylcholine ordilinolylphosphatidylcholine and especiallydipalmitoylphosphatidylcholine.

The following substances are especially suitable non-steroidalantiphlogistic substances for use in the combination proposed by theinvention:

Pyrazolones and especially

phenylbutazone (4-butyl-1,2-diphenylpyrazolidine-3,5-dion), and

oxyphenbutazone(4-butyl-2-(4-hydroxyphenyl)-1-p-phhenylpyrazolidine-3,5-dion);

Salicylic acid derivatives such as salicylic acid salicylic acid amide,

acetyl-salicylic acid,

benorilate (4-acetamidophenyl-o-acetylsalicylate), and diflunisal(5-(2,4-difluorophenyl)-salicylic acid);

Indoles, especially indometacine and its analogs such as

indometacine (1-(p-chlorobenzyyl)-5-methoxy-2-methylindole acetic acid),

glucametacine (1-(p-chlorobenzoyl-5-methoxy-2-methylindole-3- yl aceticacid glucose amide),

acemetacine (1-(p-chlorobenzoyl)-5-methoxy-3-methylindole-3- aceticacid-glycolic acid-ester), and

sulindac(5-fluor-2-methyl-1-p-(methylsulphenyl)-benzylidene-indene-3-aceticacid);

Phenyl acetic acid or phenyl propionic acid derivatives such as

ibuprofen (2-(4-isobutylphenyl)-propinic acid);

naproxen (2-(6-methoxy-2-naphthtyl)-propinic acid),

alclofenac (4-allyloxy-3-chlorophenyl-acetic acid),

ketoprofen (2-(3-benzylphenyl)-benzoic acid),

diclofenac (2-(2,6-dichlorophenylamino)-phenyl-acetic acid),

fenoprofen (2-(3-phenyloxyphenyl)-acetic acid),

tolmetin (1-methyl-5-(p-toluyl)-pyrrole-2-yl-acetic acid),

flurbiprofen (2-(2-fluorobiphenyl-4-ye-propionic acid), and

suprofen (p-2-thenoyl-hydratropic acid) phenylproprionic acid);

Anthranilic acids and their nitrogen analogs such as flufenamino acid(N-(m-trifluoromethylphenyl)-anthranilic acid),

mefenamino acid (N-(2,3-dimethylphenyl)-anthranilic acid), and

niflumin acid (2-(3-trifluoromethylaminolino)-nicotinic acid).

The novel mixture of the present invention comprising non-steroidalantiphlogistic substances and phospholipid is particularly suitable fororal application where the molar ratio of antiphlogistic substance tophospholipid ranges from about 1:0.1 to about 1:20, and preferably fromabout 1:0.5 to about 1:2.

The mixture can be prepared by dissolving the antiphlogistic substanceand the phospholipid in a suitable organic solvent such as methanol,ethanol or chloroform and by subsequently separating the solvent fromthe mixture by distillation. The antiphlogistic substance can also bedissolved in water at a suitable pH with the phospholipid being stirredinto the solution. The emulsion or solution so obtained is then freed ofwater by lyophilic treatment, with a loose powder being obtainedthereby.

The mixtures prepared in this manner can be further processed intomedicines of the various standard forms of application such as, forexample, in the form of pills, filled into a capsule or dispensed in theform of a granulate, a powder or a suspension. The medicine can furthercontain the usual quantities of carrier materials and/or diluents aswell as auxiliary substances such as starch, gelatine, agar, sugar,carboxy-methylcellulose, polyvinylalcohol, magnesium stearate, sodiumalginate and the like.

The advantageous effectiveness of the novel medicines proposed by theinvention is demonstrated by several pharmacological tests which arelisted below. The development of the ulcer was determined in accordancewith

B. J. R. Whittle, "Brit.J.Pharmakol." 55, 242-243 (1975),

L. Mariani, "Eur.J.Toxicol.Environ." 8, 335-339 (1975), and

R. Menguy & L. Desbaillets, "Proc.Soc.exp.Bio." 125, 1108.

Ten male and ten female Wistar-rats (120 to 150 grams, in weight) whichhave not fed for 16 hours, were used for these tests. The bleedingstomach ulcer was provoked by oral application of the active substance.After 3.5 hours, the animals are killed and the stomach extracted,opened along the wide curvature and stretched onto a "Styropor" plate.The mean ulcer factor of the test and of the control group aredetermined. The variation is weighted in percentages as prevention ofthe ulcer formation.

Reference substances:

chloropromazine oral ED50=104.82 mg kg/KGW

atropinesulphate oral ED50=17.06 mg kg/KGW

The results of the tests are tabulated below in Tables I to VI:

                                      TABLE I                                     __________________________________________________________________________    Influence of Phospholipon® 100 Upon Ulcer Development                     Oral Application of Acetyl-Salicylic Acid                                     (Molar Ratio of Acetyl-Salicylic Acid:Phospholipon = 2:1)                                                Variation of the Mean                                                         Ulcer Factor:                                                         Acetyl-Salicylic                                                                      Acetyl-Salicylic Acid                              Dosage    Acetyl-Salicylic                                                                       Acid with p.sup.+                                                                     With p.sup.+ Versus                                                                      Incidence of                            (mg/kg KGW)                                                                           n Acid Ulcer Index.sup.a                                                                 Ulcer Index.sup.a                                                                     Without p.sup.+ (%)                                                                      Ulcers (%)                                                                           p-Value                          __________________________________________________________________________    200     10                                                                              1.20 ± 0.20                                                                         0.30 ± 0.09                                                                        -83.33     70 resp. 20                                                                          0.001                            400     10                                                                              1.10 ± 0.50                                                                         0.70 ± 0.06                                                                        -36.36     50 resp. 70                                                                          0.10-0.01                        800     10                                                                              1.20 ± 0.20                                                                         0.70 ± 0.06                                                                        -41.67     80 resp. 70                                                                          0.01-0.001                       __________________________________________________________________________     p.sup.+ = Phospholipon® 100 (92% Phosphatidylcholin, 4%                   Lysophosphatidylcholin, 3% Neutrallipide, 1% water).                          .sup.a -x ± s.sub.x.sub.--                                            

                                      TABLE II                                    __________________________________________________________________________    Influence Upon Ulcer Development By Phospholipon®  100 With               Oral Application of Phenylbutazone                                            (Molar Ratio of Phenylbutazone:Phospholipon = 2:1)                                                         Variation of Mean                                                             Ulcer Factor:                                                                 Phenylbutazone                                   Dosage    Phenylbutazone                                                                        Phenylbutazone                                                                           With p.sup.+ Versus                                                                    Incidence of                            (mg/kg KGW)                                                                           n Ulcer Index.sup.a                                                                     With p.sup.+ Ulcer Index.sup.a                                                           Without p.sup.+ (%)                                                                    Ulcers (%)                                                                           p-Value                          __________________________________________________________________________     25     10                                                                              0.70 ± 0.05                                                                        0.30 ± 0.04                                                                           -57.14   70 resp. 30                                                                          0.02-0.01                         50     10                                                                              1.60 ± 0.42                                                                        0.90 ± 0.42                                                                           -43.75   60 resp. 40                                                                          0.01-0.001                       100     10                                                                              1.80 ± 0.84                                                                        1.20 ± 0.84                                                                           -33.33   100 resp. 90                                                                         0.02-0.01                        200     10                                                                              1.90 ± 0.66                                                                        1.20 ± 0.96                                                                           -36.84   80     0.01-0.001                       __________________________________________________________________________     p.sup.+ = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x.sub.--                                            

                                      TABLE II                                    __________________________________________________________________________    Influence Upon Ulcer Development By Phospholipon® 100                     With Oral Application of Indometacine                                         (Molar Ratio Indometacine:Phospholipon = 1:2)                                                             Variation of Mean                                                             Ulcer Factor:                                                                 Indometacine                                      Dosage    Indometacine                                                                         Indometacine                                                                             With p.sup.+ and                                                                       Incidence of                             (mg/kg KGW)                                                                           n Ulcer Index.sup.a                                                                    With p.sup.+ Ulcer Index.sup.a                                                           Without (%)                                                                            Ulcers (%)                                                                            p-Value                          __________________________________________________________________________     5      10                                                                              1.20 ± 0.30                                                                       0.20 ± 0.31                                                                           -83.33   70 resp. 20                                                                          0.02-0.01                         10      10                                                                              1.90 ± 0.90                                                                       0.40 ± 0.07                                                                           -78.95   90 resp. 40                                                                          0.001                             20      10                                                                              1.50 ± 0.40                                                                       0.50 ± 0.08                                                                           -66.67   100 resp. 50                                                                         0.001                             __________________________________________________________________________     p.sup.+ = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x.sub.--                                            

                                      TABLE IV                                    __________________________________________________________________________    Influence Upon Ulcer Development By Phospholipon® 45                      of a Rat With Oral Application of Indometacine                                (Molar Ratio of Indometacine:Phospholipon = 1:2)                                                         Variation of Mean                                                             Ulcer Factor:                                                                 Indometacine                                       Dosage    Indometacine                                                                         Indometacine With                                                                       With p.sup.+ and                                                                       Incidence of                              (mg/kg KGW)                                                                           n Ulcer Index.sup.a                                                                    Phospholipon® 45.sup.a                                                              Without (%)                                                                            Ulcers (%)                                                                           p-Value                            __________________________________________________________________________     5      10                                                                              2.10 ± 0.36                                                                       1.20 ± 0.29                                                                          -42.85   80 resp. 90                                                                          0.1-0.05                           10      10                                                                              2.20 ± 0.42                                                                       1.80 ± 0.25                                                                          -18.18   90     0.5-0.4                            20      10                                                                              2.30 ± 0.47                                                                       2.00 ± 0.36                                                                          -13.04   100    0.5                                30      10                                                                              2.70 ± 0.30                                                                       2.40 ± 0.30                                                                          -11.11   80 resp. 100                                                                         0.5-0.4                            __________________________________________________________________________     p.sup.+ = Phopholipon® 45 (45% Phosphatidylcholine, 25%                   Phosphatidylethanolamine, 12% Phosphatidylinositol, 10% Sterine, 4%           Lysophosphatidylcholine and Lysophosphatidylcholinethanolamine, 3%            Neutrallipide, 1% water)                                                      .sup.a -x ± s.sub.x.sub.--                                            

                  TABLE V                                                         ______________________________________                                        Influence Upon Ulcer Development By Phospholipon® 100                     With Oral Application of Indometacine                                         Dosage One cc per mg/kg of Body Weight (KGW))                                                                Variation of Mean                              Proportion of                  Ulcer Factor: Indo-                            Indometacine:       Indometacine                                                                             metacine With p.sup.+                          Phospholi-                                                                             Indometacine                                                                             With p.sup.+                                                                             Versus Without p.sup.+                         pon® 100                                                                           Ulcer Index.sup.a                                                                        Ulcer Index.sup.a                                                                        (%)                                            ______________________________________                                        1:0      2.60 ± 0.22                                                                           --         ±0                                          1:0.1    --         1.70 ± 0.21                                                                           -34.62                                         1:2.0    --         0.40 ± 0.07                                                                           -78.95                                         1:10.0   --         1.60 ± 0.16                                                                           -38.46                                         ______________________________________                                         p.sup.+ = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x.sub.--                                            

                                      TABLE VI                                    __________________________________________________________________________    Influence Upon Ulcer Development By Phospholipon® 100                     of a Rat With Oral Application of Ibuprofen                                   (Molar Ratio Ibuprofen:Phospholipon = 1:1)                                                                  Variation of Mean                                                             Ulcer Factor:                                                                 Ibuprofen With p.sup.+                          Dosage    Ibuprofen                                                                            Ibuprofen Ulcer Index.sup.a                                                                and       Incidence of                          (mg/kg KGW)                                                                           n Ulcer Index.sup.a                                                                    With Phospholipon® 100                                                                 Without p.sup.+ (%)                                                                     Ulcers (%)                                                                           p-Value                        __________________________________________________________________________     5      10                                                                              0.20 ± 0.13                                                                       0.20 ± 0.13                                                                             ±0     20     0.5                            10      10                                                                              0.30 ± 0.15                                                                       0.20 ± 0.13                                                                             -33.30    20 resp. 30                                                                          0.5                            20      10                                                                              0.50 ± 0.22                                                                       0.40 ± 0.16                                                                             -20.00    40 resp. 50                                                                          0.5                            30      10                                                                              0.71 ± 0.30                                                                       0.50 ± 0.22                                                                             -28.57    50 resp. 70                                                                          0.5                            __________________________________________________________________________     p.sup.+ = Phospholipon® 100 (as previously defined)                       .sup.a -x ± s.sub.x.sub.--                                            

The antiphlogistic effectiveness was determined in accordance with therat-paw-oedema test proposed by Hillebrecht (J. Hillebrecht,"Arzneimittelforschung", 4, 607 (1954).

On one hind paw of each rat (weight 200 to 250 grams) an oedema wascaused to develop by the "subplantane" application of carragenin (0.5%in a 0.9% NaCl solution) in the amount of 0.1 ml solution per paw.

After the application of the test substance, its volume not to exceed 10ml per kg of body weight, the volume of the paw is determined in anoverflow ("Ueberlauf"). After three hours the final value isascertained. The test is carried out for every dosage by using 10 testand 10 control animals of one sex and repeated with the identical numberof animals of the other sex. For the purpose of evaluation, theprevention of the oedema is expressed in percentages relative to thecontrol group.

Reference substances:

Hydrocortisoneacetate oral ED50=19.00 mg/kg/KGW

phenylbutazone oral ED50=100.00 mg/kg/KGW

indometacine oral ED50=7.24 mg/kg/KGW

The results of these tests are listed below in Tables VII and VIII:

                  TABLE VII                                                       ______________________________________                                        Comparison of the Effectiveness of Indometacine                               and an Indometacine-Phospholipon® 100 Mixture                             Applied to Rat-Paw Oedema                                                     Indometacine                                                                           Phospholipon® 100                                                                       Prevention of                                                                             Number of                                  (mg/kg p.o.)                                                                           mg/kg p.o.    Oedema (%)  Animals                                    ______________________________________                                        3.16     --            -47.3       12                                         10       --            -37.8       12                                         3.16      7.1          -39.3       12                                         10       22.4          -35.7       12                                         --       100           -4.1        18                                         ______________________________________                                    

                  TABLE VIII                                                      ______________________________________                                        Comparison of the Effectiveness of Indometacine                               and Indometacine-Phospholipon® 100 Mixtures                               Applied to Rat Paw Oedema (Dosage 10.0 mg/kg                                  KGW, 12 Animals)                                                              Time: Hours Elapsed     Indometacine-Phospholi-                               After Application       pon® 100 Molar Ratios                             of Active Substance                                                                        Indometacine                                                                             1:0.1    1:1  1:10                                    ______________________________________                                        3            32         33       55   32                                      4            40         28       41   45                                      5            28         24       26   24                                      6            27         24       32   38                                      ______________________________________                                    

The invention is additionally illustrated in connection with thefollowing Examples which are to be considered as illustrative of thepresent invention. It should be understood, however, that the inventionis not limited to the specific details of the Examples.

EXAMPLE 1

4.2 grams of phenylbutazone (13.6 mMol) are suspended in 75 ml of waterand admixed with 13.5 ml of 1n caustic soda solution. Into the clearsolution so obtained there are stirred 5.45 gram (7.8 mMol) ofPhospholipon® 100. The emuslion so obtained is treated lyophilically.The crystals produced are mixed with suitable additives, pressed intopills or filled into capsules.

EXAMPLE 2

1.5 grams (4.2 mMol) of indometacine are processed in a manner similarto that set forth in Example 1 to form a mixture with 4.1 of 1n causticsoda solution, 40 ml of water and 3.35 gram (4.2 mMol) of Phospholipon®45 and then treated lyophilically.

EXAMPLE 3

1.88 grams (10 mMol) of acetyl-salicylic acid, 10 ml of 1n caustic sodasolution, 25 ml of water and 4 grams (5 mMol) of Phospholipon® 100 areprocessed into a mixture and are then treated lyophilically.

EXAMPLE 4

Similar to Example 1, 1.88 grams (10 mMol) of acetyl-salicylic acid,1.46 grams of DL-lysine, 30 ml of water and 1.6 grams (2 mMol) ofPhospholipon® 100 are processed into a mixture and then treatedlyophilically.

EXAMPLE 5

1.43 grams (4 mMol) of indometacine and 3.2 grams (4 mMol) ofPhospholipon® 100 are dissolved in 50 ml of heated ethanol. The ethanolis then separated by distillation. The remaining substance is mixed withsuitable additives pressed into pills or filled into capsules.

EXAMPLE 6

Acetyl-salicylic acid pills:

    ______________________________________                                        acetyl-salicylic acid   216    mg                                             Phospholipon® 100   400    mg                                             aerosil                 50     mg                                             Na--carboxymethylcellulose                                                                            16     mg                                             Cuttina H®          12     mg                                             microcrystalline cellulose                                                                            150    mg                                             ______________________________________                                    

The substances listed above are mixed, pressed and the items so pressedare coated in a manner known per se with 20 mg ofhydroxypropylmethylcellulosephthalate in a coating drum.

EXAMPLE 7

Acetyl-salicylic acid capsules:

    ______________________________________                                        acetyl-salicylic acid   108 mg                                                Phospholipon® 80    200 mg                                                talcum                  3 mg                                                  magnesiumstearate       3 mg                                                  microcrystalline cellulose                                                                            100 mg                                                aerosil                 25 mg                                                 ______________________________________                                    

The substances listed above are granulated and filled into capsules (500mg hard-gelatin capsules).

In the case of the Examples 8-13, pills and capsules are manufactured ina manner similar to the Examples 1, 2 and 3 but employing othernon-steroid, inflammation-preventing substances.

EXAMPLE 8

An indometacine pill is produced from:

30 mg of indometacine and

130 mg of Phospholipon® 100

EXAMPLE 9

An indometacine pill is produced from:

30 mg of indometacine and

70 mg of Phospholipon® 100H

EXAMPLE 10

Indometacine capsules are produced containing:

30 mg of indometacine

130 mg of Phospholipon® 100

EXAMPLE 11

Phenylbutazone pills are produced containing:

105 mg of phenylbutazone

140 mg of Phospholipon® 100

EXAMPLE 12

Ibuprofen pills are produced containing:

100 mg of ibuprofen

210 mg of Phospholipon® 100

EXAMPLE 13

Acetyl-salicylic acid pills are produced containing:

220 mg of acetyl-salicylic acid

80 mg of dipalmitoylphosphatidylcholine

All the prepartions of Examples 8-13 show an improvement incompatibility and prevented side effects which normally are occurring inconnection with the active substances involved.

The principles, preferred embodiments and modes of operation of thepresent invention have been described in the foregoing specification.The invention which is intended to be protected herein, however, is notto be construed as limited to the particular forms disclosed, sincethese are to be regarded as illustrative rather than restrictive.Variations and changes may be made by those skilled in the art withoutdeparting from the spirit of the invention.

What is claimed is:
 1. A pharmaceutical composition in the form for oraladministration in the prevention of inflammation in mammals comprisingan effective inflammation-alleviating amount of at least onephospholipid and a non-steroidal inflammation-preventing compoundselected from the group consisting of salicylic acid and derivativesthereof, said phospholipid and said compound being present in a molarratio ranging from about 0.1:1 to about 20:1, respectively.
 2. Thecomposition of claim 1 wherein the inflammation-preventing compound andthe at least one phospholipid are present in molar ratios ranging fromabout 1:0.5 to about 1:2.
 3. The composition of claims 1 or 2 whereinthe at least one phhospholipid is phosphatidylcholine.
 4. Thecomposition of claims 1 or 2 wherein the at least one phospholipidcomprises phosphatidylcholine and phosphatidylinositol.
 5. Thecomposition of claims 1 or 2 wherein the inflammation-preventingcompound is salicylic acid.
 6. The composition of claim 5 wherein theinflammation-preventing compound is acetyl-salicylic acid.
 7. Thecomposition of claims 1 or 2 wherein the inflammation-preventingcompound is salicylic acid amide.
 8. The composition of claims 1 or 2wherein the inflammation-preventing compound is benorilate.
 9. Thecomposition of claims 1 or 2 wherein the inflammation-preventingcompound is difunisal.
 10. The composition of claim 7 comprising acetylsalicylic acid and phosphatidylcholine which are present in a molarratio ranging from about 1:0.2 to about 1:2.
 11. A method of alleviatinginflammation in a mammal comprising orally administering to said mammalan effective inflammation-alleviating amount of a pharmaceuticalcomposition comprising at least one phospholipid and a non-steroidalinflammation-preventing compound selected from the group consisting ofsalicylic acid and derivatives thereof, said phospholipid and saidcompound being present in a molar ratio ranging from about 0.1:1 toabout 20:1, respectively.
 12. The method of claim 11 wherein saidcompound is salicylic acid.
 13. The method of claim 11 wherein saidcompound is acetyl-salicylic acid.
 14. The method of claim 11 whereinthe at least one phospholipid is selected from the group consisting ofphosphatidylcholine, phosphatidylinositol and mixtures thereof.
 15. Themethod of claim 11 wherein said compound is salicylic acid amide. 16.The method of claim 11 wherein said compound is benorilate.
 17. Themethod of claim 11 wherein said compound is difunisal.